Interleukin-17 is a recently identified cytokine, which is secreted by activated lymphocytes. IL-17 may be involved in inflammatory processes because it is able to activate NF-kappaB with the subsequent stimulation of inflammatory cytokine expression. We have cloned the human IL-17 receptor from a human small intestinal cDNA library. In this effort we observed four variants of the human IL-17 receptor including a potential soluble IL-17 receptor. Initial experiments demonstrate that rodent and human intestinal epithelial cells express functional IL-17 receptors. The biological responses of intestinal epithelial cells to IL-17 stimulation include the regulation of transepithelial electrical resistance and the TRAF6 dependent activation of NF-kappaB with the subsequent induction of chemokine mRNA expression. However, the signal transduction mediators interacting with the IL-17 receptor upon IL-17 binding are unknown. Furthermore, the functionally significant motifs in the cytoplasmic region and the signal transducer of the mouse and human IL-17 receptors have not been identified. The overall hypothesis is that the variants of the human IL-17 receptor may regulate separate and distinct cellular responses in intestinal epithelial cells. The overall goal of this study is to characterize the biologic function of the human IL-17 receptor and the signal transduction and transcriptional activation events mediating these functions. The purpose of our experiments will be to provide an increased understanding of the signal transduction of IL-17 ligand-receptor system and its role in regulation of human intestinal epithelial cell function.